Combination antiretroviral therapy (ART) represents a medical success with few contemporary parallels. However, ART does not eradicate HIV, prevent long-term morbidities, or fully restore immune function. In addition, ART requires lifelong daily adherence, and treatment failure is common due to suboptimal adherence, drug resistance or toxicity. One approach to bridging these treatment gaps is through the development of novel, long-acting therapies as a complement to the current paradigm of daily treatment. PRO 140 is a humanized anti-CCR5 monoclonal antibody (mAb) that has demonstrated potent, long- lived antiretroviral activity and an encouraging safety profile in initial clinical testing. PRO 140 has the potential to be the first long-acting (weekly or every other week), self-administered HIV drug. Unlike small- molecule CCR5 antagonists, PRO 140 inhibits CCR5-tropic (R5) HIV through a direct rather than allosteric mechanism and preserves CCRS's natural activity. PRO 140 also broadly inhibits drug-resistant R5 viruses, including those resistant to small-molecule CCR5 antagonists. Overall, PRO 140 represents a distinct class of CCR5 inhibitor with unique virological and immunological properties. This project seeks to obtain the first clinical proof of principle for a long-acting, self-administered HIV drug. The proposed study is a randomized, double-blind, placebo-controlled trial to explore the antiviral activity, safety, PK and immunological effects of PRO 140 tested as short-term monotherapy in HIV-infected individuals with eariy-stage infection. Subjects (n=40) will self-inject PRO 140 subcutaneously using a simple push-button device. Our primary hypothesis is that HIV replication can be potently suppressed through infrequent self-use of a long-acting HIV drug. In addition, the study provides an ideal setting to explore the effects of treatment on Thi7 and other relevant subsets of CCRS^ T cells that are critical for normal host defense, are severely depleted by HIV, and are suboptimally restored by existing ART. This study will be the first to examine the effects of initiating treatment with any HIV drug on Thi7 cell numbers function and CCR5 occupancy. Success requires that treatment demonstrate potent and long-lived antiviral effects (^1.5 logio mean decrease in HIV RNA), minimal injection-site reactions, and ease of use. In our immunological analyses, success is defined as high-level (>90%) CCR5 receptor occupancy on Thi7 cells throughout the treatment period without depletion of these cells. If successful, this project will advance an innovative treatment paradigm and elucidate fundamental aspects of immune dynamics during HIV infection and therapy. RELEVANCE (See instructions): Antiretroviral therapy has dramatically improved the lives of many HIV-infected individuals; however, there remains a need for new treatment strategies to address drug resistance, long-term toxicities and other challenges. This project seeks to obtain proof of concept for an innovative CCR5 antibody used as the first long-acting, self-administered HIV drug. Success would represent a major advance towards the introduction of long-acting HIV therapies as a complement to the current paradigm of daily lifetime adherence to treatment.